Involvement of Dihydrodiols and Diol Epoxides in the Metabolic Activation of Polycyclic Hydrocarbons Other than Benzo[a]pyrene

Sims, P.; Grover, Philip L.

doi:10.1016/b978-0-12-279203-8.50009-4

Cited by 60 publications

(45 citation statements)

References 150 publications

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“…A similar effect was also observed for the N1Ade adducts of BP (7) and dibenzo[a,l]pyrene (unpublished results). 3 The spectrum in Figure 4B does not display a shielding effect of the doublet signal 4-H, suggesting that substitution of the DBC moiety takes place at C-6. The similar chemical shift of the 6-NH 2 in DBC-6-N3Ade (7.45 ppm, Figure 4B) and DBC-5-N3Ade (7.42 ppm, Figure 3B) indicates that the same nitrogen of Ade is substituted in both adducts.…”

Section: Resultsmentioning

confidence: 95%

Synthesis of Depurinating DNA Adducts Formed by One-Electron Oxidation of 7H-Dibenzo[c,g]carbazole and Identification of These Adducts after Activation with Rat Liver Microsomes

Chen

Devanesan

Byun

et al. 1997

Chem. Res. Toxicol.

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It is hypothesized that 7H-dibenzo[c,g]carbazole (DBC) is metabolically activated by one-electron oxidation in accordance with its propensity to be easily oxidized to its radical cation. Iodine oxidation of DBC produces a radical cation that subsequently binds to nucleophilic groups of dG or Ade. Oxidation of DBC in the presence of dG products three adducts: DBC-5-N7Gua, DBC-6-N7Gua, and DBC-6-C8Gua, whereas in the presence of Ade, four adducts are obtained: DBC-5-N7Ade, DBC-5-N3Ade, DBC-5-N1Ade, and DBC-6-N3Ade. Formation of these adducts demonstrates that the DBC radical cation reacts at C-5 or C-6 with the reactive nucleophiles N-7 and C-8 of dG and N-7, N-3, and N-1 of Ade. Formation DNA adducts by DBC was studied by using horesradish peroxidase or 3-methylcholanthrene-induced rat liver microsomes for activation. Identification of the biologically-formed depurinating adducts was achieved by comparison of their retention times on HPLC in two different solvent systems and by matrix-assisted laser desorption ionization (MALDI) mass spectrometry. Quantitation of the adducts formed by rat liver microsomes shows that 96% are depurinating adducts, DBC-5-N7Gua (11%), DBC-6-N7Gua (32%), and DBC-5-N7Ade (53%), and 4% are unidentified stable adducts. Activation of DBC by horseradish peroxidase affords 32% stable unidentified adducts and 68% depurinating adducts: 19% DBC-5-N7Gua, 13% DBC-6-N7Gua, 27% DBC-5-N7Ade, and 9% DBC-5-N3Ade. Thus, activation of DBC by cytochrome P450 predominantly forms depurinating adducts by one-electron oxidation.

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Section: Resultsmentioning

confidence: 95%

Synthesis of Depurinating DNA Adducts Formed by One-Electron Oxidation of 7H-Dibenzo[c,g]carbazole and Identification of These Adducts after Activation with Rat Liver Microsomes

Chen

Devanesan

Byun

et al. 1997

Chem. Res. Toxicol.

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“…the epoxide oxygen is located in a "bay" (BARTLE and JONES 1967) that is formed in a molecule by the presence of an angular benzo-ring. The detailed studies concerned have been reviewed elsewhere (see GELBOIN 1980;SIMS and GROVER 1981;CaNNEY 1982;COOPER et al 1983), and, most recently and comprehensively, by DIPPLE et al (1984). It should perhaps be mentioned that this generalisation is based on examination of one or more aspects of the metabolic activation of many different PAR ranging from phenanthrene through the benzopyrenes to the dibenzanthracenes and that there are some exceptions to the general rule (see Sect.…”

Section: Mechanisms Involved In Metabolic Activationmentioning

confidence: 98%

“…In both cases data obtained from experiments in which the activities of synthetic diols and diol-epoxides as mutagens and tumour-initiating agents were examined (see SIMS and GROVER 1981;CONNEY 1982) indicated that the bay-region diol-epoxides were the most biologically active compounds. It was therefore tempting to assume that both BA and chrysene were activated solely by conversion to the bay-region diol-epoxides.…”

Section: Benz[ajanthracene and Chrysenementioning

confidence: 98%

Polycyclic Aromatic Hydrocarbons: Metabolism, Activation and Tumour Initiation

Hall¹,

Grover²

1990

Handbook of Experimental Pharmacology

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“…For PAH, the two main types ofultimate carcinogenic intermediates, radical cations (3,4) and bay-region vicinal diol-epoxides (5,33,34), are formed by one-electron oxidation and two-electron oxidation, respectively. In this paper we will review the chemical, biochemical, and biological evidence indicating that radical cations play an important role in PAH carcinogenesis.…”

Section: Enzymology Of One-electron and Two-electron Oxidationmentioning

confidence: 99%

Role of Radical Cations in Aromatic Hydrocarbon Carcinogenesis

Cavalieri¹,

Rogan²

1985

Environmental Health Perspectives

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Carcinogenic activation of polycyclic aromatic hydrocarbons (PAH) involves two main pathways: oneelectron oxidation and monooxygenation. One-electron oxidation produces PAH radical cations, which can react with cellular nucleophiles. Results from biochemical and biological experiments indicate that only PAH with ionization potentials below ca. 7.35 eV can be metabolically activated by one-electron oxidation. In addition, the radical cations of carcinogenic PAH must have relatively high charge localization to react effectively with macromolecules in target cells. Metabolic formation of PAH quinones proceeds through radical cation intermediates. Binding of benzo[a]pyrene (BP) to mouse skin DNA occurs predominantly at C-6, the position of highest charge localization in the BP radical cation, and binding of 6-methylBP to DNA in mouse skin yields a major adduct with the 6-methyl group bound to the 2-amino group of deoxyguanosine. Studies of carcinogenicity by direct application of PAH to rat mammary gland indicate that only PAH with ionization potentials low enough for activation by one-electron oxidation produce tumors in this target tissue. These constitute some of the results which provide evidence for the involvement of one-electron oxidation in PAH carcinogenesis.

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Involvement of Dihydrodiols and Diol Epoxides in the Metabolic Activation of Polycyclic Hydrocarbons Other than Benzo[a]pyrene

Cited by 60 publications

References 150 publications

Synthesis of Depurinating DNA Adducts Formed by One-Electron Oxidation of 7H-Dibenzo[c,g]carbazole and Identification of These Adducts after Activation with Rat Liver Microsomes

Synthesis of Depurinating DNA Adducts Formed by One-Electron Oxidation of 7H-Dibenzo[c,g]carbazole and Identification of These Adducts after Activation with Rat Liver Microsomes

Polycyclic Aromatic Hydrocarbons: Metabolism, Activation and Tumour Initiation

Role of Radical Cations in Aromatic Hydrocarbon Carcinogenesis

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